acetylcysteine has been researched along with alpha-synuclein in 33 studies
Timeframe | Studies, this research(%) | All Research% |
---|---|---|
pre-1990 | 0 (0.00) | 18.7374 |
1990's | 1 (3.03) | 18.2507 |
2000's | 17 (51.52) | 29.6817 |
2010's | 12 (36.36) | 24.3611 |
2020's | 3 (9.09) | 2.80 |
Authors | Studies |
---|---|
Hashimoto, M; Hsu, LJ; Masliah, E; Takeda, A; Takenouchi, T | 1 |
Dawson, TM; Engelender, S; Igarashi, S; L Dawson, V; Rao, RK; Ross, CA; Sawa, A; Tanaka, Y; Tanzi, RE; Wanner, T | 1 |
Boeddrich, A; Lehrach, H; Lueder, G; Lurz, R; Scherzinger, E; Waelter, S; Wanker, EE | 1 |
Larsen, KE; Rideout, HJ; Stefanis, L; Sulzer, D | 1 |
Lehmensiek, V; Schwarz, J; Storch, A; Tan, EM | 1 |
Junn, E; Kim, YM; Lee, G; Mouradian, MM; Tanaka, M | 1 |
Berger, K; Cookson, MR; Eberhardt, O; Engelender, S; Farrer, MJ; Gerhardt, E; Hernandez, D; Holzmann, C; Kachergus, J; Krüger, R; Li, L; Marx, FP; Riess, O; Ross, CA; Schöls, L; Schulz, JB; Strauss, KM | 1 |
Halliwell, B; Hyun, DH; Jenner, P; Lee, M | 1 |
Akaike, A; Ibi, M; Inden, M; Izumi, Y; Kihara, T; Kitamura, Y; Kohno, R; Nakamizo, T; Nakanishi, M; Sakka, N; Sawada, H; Shibasaki, H; Shimohama, S; Taniguchi, T; Yamakawa, K; Yamamoto, N | 1 |
Dauer, WT; Dietrich, P; Rideout, HJ; Stefanis, L; Wang, Q | 1 |
Lang-Rollin, IC; Rideout, HJ; Savalle, M; Stefanis, L | 1 |
Hahn, JS; Kim, HY; Kim, M; Lee, IH; Paik, SR | 1 |
Ballard, C; Iravani, MM; Jenner, P; MacInnes, N; Perry, E; Perry, R; Piggott, M | 1 |
Bonham, CC; Davisson, VJ; Hindupur, J; Liu, F; Nguyen, JL; Rochet, JC; Ruf, KJ; Schieler, JL; Wood, KV; Zhu, J | 1 |
Kerk, SY; Lim, TM; Xiong, GG; Zhou, ZD | 1 |
Fu, X; Mei, J; Niu, C; Pan, Q | 1 |
Qiao, L; Zhang, J | 1 |
Chen, B; Xu, SL; Zhou, M | 1 |
Johansson, SM; Modo, MM; Vernon, AC | 1 |
Adame, A; Clark, J; Clore, EL; Masliah, E; Simon, DK; Zheng, K | 1 |
Arawaka, S; Fukushima, S; Hara, S; Kato, T; Koyama, S; Machiya, Y; Sakamoto, M; Sato, H | 1 |
Caruana, M; Giese, A; Hillmer, A; Högen, T; Levin, J; Vassallo, N | 1 |
Bajic, N; Ballard, CG; Francis, PT; Jenner, P | 1 |
Benke, S; Broeskamp, F; Büttner, S; Callewaert, G; Carmona-Gutierrez, D; D'hooge, P; Eisenberg, T; Faes, L; Franssens, V; Freudenberger, P; Ghillebert, R; Habernig, L; Harger, A; Kourtis, N; Kroemer, G; Madeo, F; Pieber, TR; Reichelt, WN; Ruli, D; Sigrist, SJ; Tavernarakis, N; Winderickx, J | 1 |
Dryanovski, DI; Galteri, DJ; Guzman, JN; Lee, VM; Miller, RJ; Schumacker, PT; Surmeier, DJ; Volpicelli-Daley, LA; Xie, Z | 1 |
Bai, L; Chen, Q; Hu, X; Wu, J; Zhang, H; Zhang, L; Zhang, Y | 1 |
Anand, S; Banerjee, P; Bir, A; Cappai, R; Chakrabarti, S; Khemka, VK; Sahoo, A; Sen, O | 1 |
Elson, JL; Pienaar, IS; Yates, A | 1 |
Myöhänen, TT; Norrbacka, S; Savolainen, MH | 1 |
Chong, W; Jiménez, J; Kwakye, GF; McIIvin, M; Saito, MA | 1 |
Goldstein, DS; Isonaka, R; Jinsmaa, Y; Sharabi, Y | 1 |
Brandel, J; Dexter, DT; Elson, JL; Fairooz, S; Hubscher-Bruder, V; Lewis, FW; Pienaar, IS; Smith, D; Soundararajan, M; Tétard, D | 1 |
Du, Y; Guan, Y; Hao, Y; Le, W; Li, Z; Song, Y; Wang, F; Yang, X | 1 |
33 other study(ies) available for acetylcysteine and alpha-synuclein
Article | Year |
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Role of cytochrome c as a stimulator of alpha-synuclein aggregation in Lewy body disease.
Topics: Acetylcysteine; alpha-Synuclein; Antioxidants; Brain; Cytochrome c Group; Deferoxamine; Humans; Hydrogen Peroxide; Immunohistochemistry; Lewy Body Disease; Nerve Tissue Proteins; Oxidative Stress; Recombinant Proteins; Synucleins | 1999 |
Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Apoptosis; Blotting, Western; Caspase 3; Caspase 9; Caspases; Cyclosporine; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Gene Expression Regulation; Immunoenzyme Techniques; Membrane Potentials; Mitochondria; Multienzyme Complexes; Mutation; Nerve Tissue Proteins; Parkinson Disease; PC12 Cells; Proteasome Endopeptidase Complex; Rats; Synucleins; Tetracycline; Transfection | 2001 |
Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation.
Topics: 14-3-3 Proteins; Acetylcysteine; alpha-Synuclein; Carrier Proteins; Cell Line; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Endoplasmic Reticulum Chaperone BiP; Exons; Heat-Shock Proteins; Humans; Huntingtin Protein; Huntington Disease; Immunoblotting; Inclusion Bodies; Membrane Proteins; Microscopy, Fluorescence; Models, Biological; Molecular Chaperones; Multienzyme Complexes; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Peptide Fragments; Poly(A)-Binding Proteins; Proteasome Endopeptidase Complex; Proteins; Recombinant Fusion Proteins; RNA-Binding Proteins; Synucleins; T-Cell Intracellular Antigen-1; Transgenes; Tyrosine 3-Monooxygenase; Vimentin | 2001 |
Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells.
Topics: Acetylcysteine; alpha-Synuclein; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Cell Differentiation; Cyclic AMP; Cysteine Endopeptidases; Immunoblotting; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Multienzyme Complexes; Nerve Tissue Proteins; Neuroprotective Agents; Oligopeptides; Parkinson Disease; PC12 Cells; Protease Inhibitors; Proteasome Endopeptidase Complex; Rats; Synucleins; Ubiquitins | 2001 |
Expression of mutant alpha-synucleins enhances dopamine transporter-mediated MPP+ toxicity in vitro.
Topics: 1-Methyl-4-phenylpyridinium; Acetylcysteine; alpha-Synuclein; Cell Line; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dopamine Plasma Membrane Transport Proteins; Gene Expression; Herbicides; Humans; In Vitro Techniques; Kidney; Membrane Glycoproteins; Membrane Transport Proteins; Multienzyme Complexes; Mutagenesis; Nerve Tissue Proteins; Proteasome Endopeptidase Complex; Rotenone; Synucleins; Transfection; Uncoupling Agents | 2002 |
Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Blotting, Western; Carrier Proteins; Cell Line; Cell Survival; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dimethyl Sulfoxide; Humans; Inclusion Bodies; Intracellular Signaling Peptides and Proteins; Kidney; Leupeptins; Macromolecular Substances; Mice; Multienzyme Complexes; Nerve Tissue Proteins; Neuroblastoma; Precipitin Tests; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Synucleins; Transfection; Ubiquitin | 2002 |
Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease.
Topics: Acetylcysteine; Adult; Aged; alpha-Synuclein; Amino Acid Sequence; Carrier Proteins; Case-Control Studies; Cell Death; Cells, Cultured; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Green Fluorescent Proteins; Humans; Luminescent Proteins; Male; Middle Aged; Molecular Sequence Data; Multienzyme Complexes; Mutation; Nerve Tissue Proteins; Neurons; Parkinson Disease; Proteasome Endopeptidase Complex; Recombinant Fusion Proteins; Staurosporine; Synucleins; Ubiquitin-Protein Ligases | 2003 |
Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins.
Topics: Acetylcysteine; alpha-Synuclein; Cell Line; Cell Survival; Cysteine Endopeptidases; Enzyme Inhibitors; Gene Transfer Techniques; Humans; Ligases; Macromolecular Substances; Multienzyme Complexes; Nerve Tissue Proteins; Neurofilament Proteins; Nitrates; Nitric Oxide Synthase; Proteasome Endopeptidase Complex; Proteins; Superoxide Dismutase; Superoxide Dismutase-1; Synucleins; Tubulin; Ubiquitin; Ubiquitin-Protein Ligases | 2003 |
Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions.
Topics: 1-Methyl-4-phenylpyridinium; Acetylcysteine; alpha-Synuclein; Animals; Brain; Caspase 3; Caspase Inhibitors; Caspases; Cysteine Endopeptidases; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Herbicides; Immunoblotting; Immunohistochemistry; Ions; L-Lactate Dehydrogenase; Leupeptins; Male; MAP Kinase Signaling System; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Multienzyme Complexes; Nerve Tissue Proteins; Neurons; Phosphorylation; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Rotenone; Synucleins; Time Factors; Ubiquitin | 2004 |
alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Apoptosis; Benzothiazoles; Blotting, Western; Cells, Cultured; Cytoplasm; Genotype; Lewy Bodies; Mice; Mice, Knockout; Microscopy, Fluorescence; Nerve Tissue Proteins; Neurons; Protease Inhibitors; Proteasome Inhibitors; Rats; Synucleins; Thiazoles; Time Factors; Ubiquitin | 2004 |
Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up-regulate iHSP70, following proteasomal inhibition.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Apoptosis; Cells, Cultured; Dopamine; HSP70 Heat-Shock Proteins; Inclusion Bodies; Mesencephalon; Nerve Tissue Proteins; Neurons; Oligopeptides; Proteasome Inhibitors; Rats; Synucleins; Transcription, Genetic; Ubiquitin; Up-Regulation | 2005 |
Dequalinium-induced cell death of yeast expressing alpha-synuclein-GFP fusion protein.
Topics: Acetylcysteine; alpha-Synuclein; Anti-Infective Agents, Local; Benzimidazoles; Blotting, Western; Dequalinium; Fluorescent Dyes; Green Fluorescent Proteins; Organic Chemicals; Plasmids; Proteasome Inhibitors; Recombinant Fusion Proteins; Saccharomyces cerevisiae; Yeasts | 2008 |
Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems.
Topics: Acetylcholine; Acetylcysteine; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Basal Nucleus of Meynert; Cell Death; Cells, Cultured; Cerebral Cortex; Cholinergic Fibers; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Rats; Rats, Sprague-Dawley; Ubiquitin | 2008 |
Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Antioxidants; Blotting, Western; Cell Death; Cells, Cultured; Cysteine Proteinase Inhibitors; Dopamine; Humans; Leupeptins; Mesencephalon; Methionine Sulfoxide Reductases; Mice; Neurons; Oxidation-Reduction; Oxidoreductases; Parkinson Disease; Rats; Rotenone; Uncoupling Agents; Vitamin E | 2008 |
Dopamine auto-oxidation aggravates non-apoptotic cell death induced by over-expression of human A53T mutant alpha-synuclein in dopaminergic PC12 cells.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Benzimidazoles; Cell Death; Chromatography, High Pressure Liquid; Cysteine; Dopamine; Enzyme Inhibitors; Flow Cytometry; Fluorescent Dyes; Free Radical Scavengers; Glutathione; Humans; Monophenol Monooxygenase; Mutation; Nerve Growth Factor; Oxidation-Reduction; PC12 Cells; Rats; Tetrazolium Salts; Thiazoles; Transfection | 2009 |
Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Behavior, Animal; Corpus Striatum; Cysteine Proteinase Inhibitors; Disease Models, Animal; Hypokinesia; Inclusion Bodies; Male; Microscopy, Electron, Transmission; Motor Activity; Neurodegenerative Diseases; Neurons; Proteasome Inhibitors; Rats; Rats, Sprague-Dawley; Substantia Nigra; Tyrosine 3-Monooxygenase | 2009 |
Inhibition of lysosomal functions reduces proteasomal activity.
Topics: Acetylcysteine; alpha-Synuclein; Ammonium Chloride; Autophagy; Blotting, Western; Cell Line, Tumor; Chloroquine; Enzyme Inhibitors; HSC70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Hydrogen-Ion Concentration; Lysosomes; Neurons; Proteasome Endopeptidase Complex | 2009 |
[Dual effects of different concentrations of alpha-synuclein on the neurotoxicity of 6-hydroxydopamine in SH-SY5Y cells].
Topics: Acetylcysteine; alpha-Synuclein; Apoptosis; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Neurons; Neuroprotective Agents; Neurotoxins; Oxidopamine; Parkinson Disease | 2009 |
Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Apomorphine; Corpus Striatum; Cysteine Proteinase Inhibitors; Disease Models, Animal; Dopamine; Dopamine Agonists; Iron; Magnetic Resonance Imaging; Male; Mesencephalon; Motor Activity; Neurons; Parkinsonian Disorders; Random Allocation; Rats; Rats, Sprague-Dawley; Substantia Nigra | 2010 |
Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.
Topics: Acetylcysteine; Administration, Oral; alpha-Synuclein; Animals; Cytosol; Dietary Supplements; Dopamine; Gene Expression; Glutathione; Humans; Male; Mice; Mice, Transgenic; Motor Activity; Neostriatum; Neuroprotective Agents; NF-kappa B; Parkinson Disease; Protein Transport; Proto-Oncogene Proteins c-sis; Time Factors; Tyrosine 3-Monooxygenase | 2010 |
Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Cell Line, Tumor; Cerebral Cortex; Cycloheximide; Cysteine Proteinase Inhibitors; Humans; Leupeptins; Lewy Bodies; Neurons; Okadaic Acid; Parkinson Disease; Phosphorylation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Phosphatase 1; Protein Phosphatase 2; Protein Synthesis Inhibitors; Rabbits; Ubiquitin | 2010 |
Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds.
Topics: Acetylcysteine; alpha-Synuclein; Antioxidants; Apigenin; Ascorbic Acid; Deferoxamine; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Humans; Iron Chelating Agents; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Structure; Mutation; Parkinson Disease; Phenols; Polyphenols; Protein Multimerization; Protein Structure, Quaternary; Recombinant Proteins; Spectrometry, Fluorescence; Structure-Activity Relationship | 2011 |
Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Blotting, Western; Cells, Cultured; Cysteine Proteinase Inhibitors; Immunohistochemistry; Lewy Body Disease; Neurons; Neuropeptides; Oligopeptides; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Synapses; Synaptophysin; Tubulin; Ubiquitination | 2012 |
The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Apoptosis; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcium; Calcium-Transporting ATPases; Humans; Manganese; Models, Biological; Molecular Chaperones; Oxidative Stress; Parkinson Disease; Phosphorylation; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins | 2013 |
Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Animals, Newborn; Calbindins; Calcium; Calcium Channels, L-Type; Cells, Cultured; Coculture Techniques; Dendrites; Dopaminergic Neurons; Free Radical Scavengers; Green Fluorescent Proteins; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; NG-Nitroarginine Methyl Ester; Oxidation-Reduction; Oxidative Stress; Patch-Clamp Techniques; Reactive Oxygen Species; RNA, Messenger; S100 Calcium Binding Protein G; Statistics, Nonparametric; tert-Butylhydroperoxide; Tyrosine 3-Monooxygenase | 2013 |
Differential protein profile of PC12 cells exposed to proteasomal inhibitor lactacystin.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Cell Death; Cytoplasm; Heat-Shock Proteins; Inclusion Bodies; Parkinson Disease; PC12 Cells; Proteasome Inhibitors; Proteome; Rats; Tyrosine 3-Monooxygenase | 2014 |
α-Synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: implications in the pathogenesis of Parkinson's disease.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Cell Death; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Parkinson Disease; Rats, Wistar | 2014 |
Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Cell Count; Choline O-Acetyltransferase; Cholinergic Neurons; Disease Models, Animal; Dopaminergic Neurons; Male; Microglia; Neurons; Parkinson Disease; Parkinsonian Disorders; Pars Compacta; Pedunculopontine Tegmental Nucleus; Protein Aggregation, Pathological; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase | 2016 |
Prolyl oligopeptidase inhibition attenuates the toxicity of a proteasomal inhibitor, lactacystin, in the alpha-synuclein overexpressing cell culture.
Topics: Acetylcysteine; alpha-Synuclein; Autophagy; Cell Line, Tumor; Cell Survival; Humans; Mutation; Proline; Prolyl Oligopeptidases; Proteasome Inhibitors; Protein Aggregates; Serine Endopeptidases; Serine Proteinase Inhibitors | 2017 |
α-Synuclein Enhances Cadmium Uptake and Neurotoxicity via Oxidative Stress and Caspase Activated Cell Death Mechanisms in a Dopaminergic Cell Model of Parkinson's Disease.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Cadmium Chloride; Caspases; Cation Transport Proteins; Cell Death; Cell Line, Transformed; Dopaminergic Neurons; Dose-Response Relationship, Drug; Endocytosis; Gene Expression Regulation; Humans; Metallothionein 3; Nerve Tissue Proteins; Neuroprotective Agents; Oncogene Protein v-akt; Oxidative Stress; Rats; Signal Transduction; Time Factors | 2017 |
3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing
Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcysteine; alpha-Synuclein; Antioxidants; Cell Line; Copper; Dopamine; Humans; Monoamine Oxidase; Monophenol Monooxygenase; Oligodendroglia; Oxidation-Reduction; Parkinson Disease; Protein Binding; Protein Conformation; Tolcapone | 2020 |
Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson's disease.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Dopamine; Dopaminergic Neurons; Humans; Iron; Iron Chelating Agents; Neuroprotective Agents; Parkinson Disease; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Substantia Nigra; Ubiquitin | 2020 |
HDAC6-mediated Hsp90 deacetylation reduces aggregation and toxicity of the protein alpha-synuclein by regulating chaperone-mediated autophagy.
Topics: Acetylcysteine; alpha-Synuclein; Animals; Chaperone-Mediated Autophagy; Histone Deacetylase 6; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Parkinsonian Disorders; Protein Aggregates | 2021 |